LIF is a polyfunctional glycoprotein with diverse actions on a broad range of tissue and cell types, including induction of differentiation in a number of myeloid leukaemic cell lines, suppression of differentiation in normal embryonic stem cells, stimulation of proliferation of osteoblasts and DA-1 haemopoietic cells and potentiation of the of the proliferative action of interleukin-3 (IL-3) on megakaryocyte precursors. Functionally, LIF is able to switch autonomic nerve signalling from adrenergic to cholinergic mode, stimulate calcium release from bones, stimulate the production of acute phase proteins by hepatocytes and induce loss of fat deposits by inhibiting lipoprotein lipase-mediated lipid transport into adipocytes.
With a potentially broad range of clinical applications, it is imperative that compositions containing LIF are presented in a stable form and remain so during an extended period which may include shipment, handling and storage. Thus, a stable composition is one which retains its physical, chemical, therapeutic and toxicological profile over this period.
Deamidation is the most significant chemical degradation of LIF over time. It is clearly desirable that this process is minimized. Adsorption of LIF onto surfaces of containers, vials, syringes and infusion tubing is also a potential problem and must be minimized to ensure accurate dose and concentration. Physical degradation, such as aggregation or flocculation, may occur due to denaturation caused by elevated temperatures and/or agitation and excessive handling of the composition. Such degradation is clearly undesirable in terms of appearance and more importantly, consistent and effective administration of LIF in clinical applications. Storage at temperatures below room temperature typically retards chemical degradation, with storage in the frozen state being generally the most effective. Whilst this may minimize chemical degradation, the process of thawing the composition may then result in aggregation.
Thus, there exists a need for a stable composition and, in particular, a stable pharmaceutical composition of LIF and/or its derivatives or homologues wherein chemical and physical degradation is minimised.